Download Alvimopan Provides Additional Improvement in Outcomes and Cost

ANNSURG-D-15-00873; Total nos of Pages: 6;
ANNSURG-D-15-00873
ORIGINAL ARTICLE
Alvimopan Provides Additional Improvement in Outcomes and
Cost Savings in Enhanced Recovery Colorectal Surgery
Mohamed Abdelgadir Adam, MD, Lacey M. Lee, PharmD, BCPS,y Jina Kim, MD, Mithun Shenoi, MD, PhD, Mohan Mallipeddi, MD, Hamza Aziz, MD, Sandra Stinnett, DPH,z Zhifei Sun, MD, Christopher R. Mantyh, MD, and Julie K. M. Thacker, MD Objective: To examine the impact of alvimopan on outcomes and costs in a
rigorous enhanced recovery colorectal surgery protocol.
Background: Postoperative ileus remains a major source of morbidity and
costs in colorectal surgery. Alvimopan has been shown to reduce incidence of
postoperative ileus in enhanced recovery colorectal surgery; however, data are
equivocal regarding its benefit in reducing length of stay and costs.
Methods: Patients undergoing major elective enhanced recovery colorectal
surgery were identified from a prospectively-collected database (2010–2013).
Multivariable analyses were employed to compare outcomes and hospital
costs among patients who had alvimopan versus no alvimopan by adjusting
for demographic, clinical, and treatment characteristics.
Results: A total of 660 patients were included; 197 patients received alvimopan and 463 patients had no alvimopan. In unadjusted analysis, the
alvimopan group had a faster return of bowel function, shorter length of
stay, and lower rates of ileus, Foley re-insertion, and urinary tract infection (all
P < 0.01). After adjustment, alvimopan was associated with a faster return of
bowel function by 0.6 day (P ¼ 0.0006), and lower incidence of postoperative
ileus (odds ratio 0.23, P ¼ 0.0002). With adjustment, alvimopan was associated with a shorter length of stay by 1.6 days (P ¼ 0.002), and a hospital cost
savings of $1492 per patient (P ¼ 0.01).
Conclusions: Alvimopan administration as an element of enhanced recovery
colorectal surgery is associated with faster return of bowel function, lower
incidence of postoperative ileus, shorter hospitalization, and a significant cost
savings. These results suggest that alvimopan is cost-effective in the setting of
enhanced recovery colorectal surgery protocols, and should therefore be
considered in these programs.
Keywords: alvimopan, colorectal surgery, entereg, enhanced recovery after
surgery
(Ann Surg 2015;xx:xxx–xxx)
P
ostoperative ileus is a frequent occurrence after colorectal
surgery, representing a major source of postoperative morbidity,
prolonged hospitalization, increased resource use, and higher
costs.1 –3 Although the pathogenesis of postoperative ileus is multifactorial, endogenous and exogenous opioids play a central role in
the development of postoperative ileus. Endogenous opioids released
in response to stress of surgery and exogenous opioids administered
for pain control can activate mu-opioid receptors in the gastrointestinal tract, resulting in decreased gastrointestinal motility.4 –6
Enhanced recovery colorectal surgery programs have been
implemented to optimize perioperative care and reduce complications such as postoperative ileus.7,8 These programs employ a
multimodal approach aiming at reduction of perioperative stress,
through patient care elements, including utilization of minimally
invasive techniques, adjunct nonopioids medications, early postoperative feeding and early mobilization. Accumulating evidence
suggest that implementation of enhanced recovery protocols in
colorectal surgery is associated with earlier recovery of gastrointestinal function with significant reduction in incidence of postoperative
ileus and hospital length of stay by 2 days for both open and
laparoscopic procedures.9– 13
Alvimopan is a peripherally acting mu-opioid receptor
antagonist that blocks the gastrointestinal effects of opioids while
preserving the central analgesic effect of administered opioids.
Alvimopan has been shown to prevent postoperative ileus and
promote recovery of gastrointestinal function after bowel resection
with primary anastomosis in up to half of the patients.14,15 Despite
these proven benefits of alvimopan in bowel surgery in general, its
utility in the setting of enhanced recovery colorectal surgery remains
to be seen. Colorectal surgery patients on enhanced recovery protocols are well optimized with care plans created to minimize
physiologic causes of ileus. Opinions that alvimopan may not
provide significant improvement to this optimized population have
been reported.16 Further, concerns were also raised with regard to the
cost of alvimopan, with an estimated cost of >$1000 for a 7-day
course. In the absence of a clinically significant improvement
provided by alvimopan, use of this medication may not be costeffective.
Published data examining the role of alvimopan in the setting
of enhanced recovery colorectal surgery protocols are inconsistent in
determining the effect of alvimopan on hospital length of stay and
costs.17–19 Generally, these studies were limited by sample size,
which precluded adequate multivariable adjustment for important
confounders. Therefore, we sought to examine the impact of alvimopan on clinical outcomes, hospital length of stay, and costs in a
large cohort of patients undergoing major enhanced recovery colorectal surgery.
METHODS
Data Source
From the Department of Surgery, Duke University Medical Center, Durham, NC;
yDepartment of Pharmacy, Duke University Medical Center, Durham, NC; and
zDepartment of Biostatistics, Duke University, Durham, NC.
The authors declare no financial conflicts of interest.
Reprints: Julie K. M. Thacker, MD, Department of Surgery, Duke University
Medical Center, Rm 7678 HAFS, DN, Durham, NC 27710.
E-mail: [email protected].
Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0003-4932/14/26105-0821
DOI: 10.1097/SLA.0000000000001428
Annals of Surgery Volume XX, Number X, Month 2015
Patients undergoing major elective colorectal surgery under
enhanced recovery protocol at Duke University Medical Center
between February 2010 and May 2013 were identified from a
prospectively collected database. Data for all patients undergoing
major elective colorectal surgery under enhanced recovery protocol
are recorded prospectively by a trained surgical reviewer. Data
accuracy is ensured through internal auditing. Patients undergoing
the following procedures were included in the study: segmental
colectomy, total abdominal colectomy, total abdominal colectomy
www.annalsofsurgery.com | 1
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
ANNSURG-D-15-00873; Total nos of Pages: 6;
ANNSURG-D-15-00873
Adam et al
with ileostomy, total proctocolectomy with ileoanal pouch, low
anterior resection, and abdominoperineal resection. All procedures
were elective and performed by 1 of 3 board-certified colorectal
surgeons.
Patient age, sex, race, body mass index (BMI), American
Society of Anesthesiologists (ASA) score, diagnosis, year of the
procedure, history of opioid use, use of thoracic epidural analgesia
and laparoscopy, and extent of resection were extracted from the
dataset. Data on perioperative outcomes, such as time to return to
bowel function, postoperative ileus, postoperative urinary tract infection, length of hospital stay, and 30-day readmission were obtained
from the dataset. Postoperative ileus was defined as re-insertion of
nasogastric tube in the absence of other indications, such as mechanical
obstruction and intubation. Length of stay was calculated from the day
of the procedure to discharge. Variable direct costs for the index
admission were obtained from our finance department. Variable direct
costs account for costs incurred during a hospital stay related to care
provided to the patient but exclude utilities and physician fees. Variable
direct costs were grouped into: (1) surgery costs (eg, operating room
time and equipment), (2) pharmacy-related costs (eg, pharmaceutical
agents), (3) diagnostic costs (eg, laboratory and radiology tests), (4)
patient care costs (eg, nursing), and (4) total hospital costs.
Annals of Surgery Volume XX, Number X, Month 2015
Statistical Analysis
The cohort was analyzed into 2 groups—patients who had
alvimopan treatment and those who did not receive alvimopan
(control). Patient demographic, clinical, and other treatment characteristics were compared between the alvimopan treatment versus
control groups using the Fisher’s exact/x2 and Kruskal–Wallis tests.
Short-term outcomes were compared between alvimopan
versus control using multivariable regression analyses by adjusting
for patient age, sex, race, BMI, ASA score, diagnosis, history of
opioid use, year of procedure, extent of surgery, use of laparoscopy
and epidural, and the operating surgeon. Multivariable logistic
regression modeling was used to analyze dichotomous outcome
variables such as rates of postoperative ileus and 30-day readmission.
Multivariable linear regression modeling was used to examine time
to return of bowel function, length of stay, and hospital costs. After
adjustment for the covariates, the predicted means of the outcomes
based on the model were obtained for the 2 groups. When the log
transformation of the outcome was used to model the data, the
predicted means were exponentiated to obtain predicted values.
The level of statistical significance was set a priori at a two-sided
P value of <0.05. Statistical analyses were performed using SAS 9.3
(SAS Institute Inc, Cary, NC).
RESULTS
Enhanced Recovery Colorectal Surgery Protocol
The Duke Enhanced Recovery Program was initially based on
the principles presented by the Enhanced Recovery After Surgery
(ERAS) Society.13,20,21 Modifications with inclusion of the anesthetic components detailed in the NICE program from the UK and
other specific to the care practices of the US have been incorporated.22 The essential Duke protocol and reported improvements in
outcomes has been previously published.13 Before surgery, patients
are educated on the components of the program and on expectations
with regard to the patient’s role. Preoperative fasting is minimized;
clear liquids are allowed up to 2 hours before surgery, and a
carbohydrate-rich beverage is prescribed at 3 hours before anesthesia
induction time.23 All patients receive preoperative antibiotic and
thromboembolic prophylaxis. Multimodal pain management is
begun in the preoperative space, as is multimodal prevention of
postoperative nausea and vomiting.24 Intraoperatively, goal-directed
fluid administration is employed with the use of esophageal Doppler
or noninvasive hemodynamic monitoring devices.25 Epidural analgesia and minimally invasive surgical approach are used when
appropriate. Postoperatively, patients are immediately allowed a diet
and are encouraged to ambulate on day of surgery. Intravenous fluid
and opioids are minimized by encouraging oral hydration and use of
adjunct analgesics, respectively. Then patient is deemed suitable for
discharge when oral intake is adequate to maintain hydration, and
pain control is adequate with an oral regimen. Before discharge, the
patient is counseled with postdischarge expectations and understanding of issues that would require contacting the surgical team
and/or presentation to the emergency department. Finally, in addition
to receiving postoperative venous thromboembolism (VTE) prophylaxis when in the hospital, the patient is prescribed VTE prophylaxis
after discharge.
Alvimopan was not part of our early institutional enhanced
recovery protocol, and its use was based on surgeon preference and/
or availability. When prescribed, a single dose of alvimopan 12 mg
orally was given preoperatively, followed by a 12 mg orally every
12 hours until first bowel movement or for a maximum of 7 days.
Patients who received at least a preoperative dose and 1 dose postoperatively were included. Those who had only 1 dose of the
medication were excluded (n ¼ 16 patients). Data on timing and
dosage of alvimopan administration were confirmed from the nursing medication administration sheets.
2 | www.annalsofsurgery.com
A total of 660 patients underwent major elective colorectal
resections between 2010 and 2013 at our institution. Of these, 197
patients received alvimopan treatment, and 463 were not treated with
alvimopan. Patient age, sex, race, BMI, and ASA scores were not
different between the 2 groups. Indications for surgery were similar
between the 2 groups (Table 1). Compared with control, patients
treated with alvimopan were more often to undergo a segmental
colectomy (61% vs 51%, P ¼ 0.048) and a laparoscopic approach
(64% vs 56%, P ¼ 0.047).
Short-term Outcomes
Median number of alvimopan doses given was 6 doses per
patient (interquartile range 4–8 doses). In unadjusted analysis,
patients treated with alvimopan versus control had lower rates of
postoperative ileus (5% vs 16%, P < 0.0001), re-insertion of indwelling Foley catheter (7% vs 14%, P ¼ 0.008), and postoperative
urinary tract infection (5% vs 12%, P ¼ 0.005). Compared with
control, the alvimopan group had a shorter hospital length of stay
(median 4 vs 5 days, P ¼ 0.0002) and a similar rate of 30-day
readmissions (10% vs 12%, P ¼ 0.35) (Table 2).
After adjustment for patient’s demographics, ASA score,
diagnosis, year of surgery, extent of surgery, and use of epidural
and laparoscopy, alvimopan treatment versus control was associated
with a significantly faster return of bowel function (0.6 days,
P ¼ 0.0006), lower likelihood of postoperative ileus [odds ratio
(OR) 0.23, 95% confidence interval (CI) 0.11–0.50, P ¼ 0.0002),
and shorter hospital length of stay (1.6 days, P ¼ 0.002) (Table 3).
Hospital Costs
Compared with control, patients treated with alvimopan had
lower patient care costs (median $1890 vs $2349, P ¼ 0.0002),
pharmacy costs ($722 vs $786, P ¼ 0.04), and total variable direct
hospital costs (median $8749 vs $9507, P ¼ 0.02) (Table 4). After
adjustment for patient demographics, ASA score, diagnosis, year of
surgery, extent of surgery, use of laparoscopy or epidural, and
operating surgeon, alvimopan treatment versus control was associated with reduced patient care costs ($1261, P < 0.0001), pharmacy costs ($187, P ¼ 0.03), and total variable direct hospital costs
($1492, P ¼ 0.01); operative costs were similar between the 2
groups (P ¼ 0.57) (Fig. 1).
ß
2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
ANNSURG-D-15-00873; Total nos of Pages: 6;
ANNSURG-D-15-00873
Annals of Surgery Volume XX, Number X, Month 2015
Alvimopan in Enhanced Recovery Colorectal Surgery
TABLE 1. Patient Demographic, Clinical, and Treatment Characteristics by Alvimopan Treatment
Control (N ¼ 463)
Alvimopan (N ¼ 197)
P Value
58 15
231 (50%)
59 15
111 (56%)
0.49
0.15
0.70
347 (75%)
99 (21%)
16 (4%)
29 6
143 (73%)
48 (24%)
6 (3%)
28 6
23 (5%)
148 (32%)
292 (63%)
6 (3%)
72 (37%)
119 (60%)
94 (20%)
64 (14%)
305 (66%)
44 (22.3%)
20 (10.2%)
133 (67.5%)
200 (43%)
149 (32%)
93 (20%)
21 (5%)
30 (6%)
416 (90%)
0
32 (16%)
107 (54%)
58 (29%)
9 (5%)
175 (89%)
236
23
18
35
124
27
258
121 (61%)
9 (5%)
5 (3%)
9 (5%)
36 (18%)
17 (9%)
126 (64%)
Patient age (years, mean SD)
Male sex
Race
White
Black
Others
BMI (mean SD)
ASA score
1
2
3
Diagnosis
Benign
Inflammatory
Neoplastic
Year of procedure
2010
2011
2012
2013
History of opioid use
Epidural placement
Procedure
Segmental colectomy
Total colectomy
Total colectomy with ileostomy
Total proctocolectomy with ileoanal pouch
Low anterior resection
Abdominoperineal resection
Laparoscopic approach
0.55
0.33
0.41
<0.0001
(51%)
(5%)
(4%)
(8%)
(27%)
(6%)
(56%)
0.37
0.79
0.05
0.047
ASA indicates American Society of Anesthesiologists; BMI, body mass index; SD, standard deviation.
Subset Analysis
Patients with prior history of opioid use were included in the
analysis. Given that alvimopan is contraindicated in a subset of
patients with history of opioid use (patients taking therapeutic doses
of opioids for more than 7 consecutive days immediately before
taking alvimopan), we performed a sensitivity analysis in which we
excluded patients with a prior history of opioid use. After adjustment
for patient, clinical, and treatment characteristics, use of alvimopan
remained significantly associated with shorter hospital length of stay
(adjusted means 8.5 vs 9.8 days, P ¼ 0.008) and reduced hospital
costs (adjusted means $14,998 vs $16,213, P ¼ 0.03).
DISCUSSION
This large, single-institution study examined the impact of
alvimopan treatment on clinical outcomes and hospital costs in 660
patients undergoing major elective colorectal surgery under a
rigorous enhanced recovery protocol. After adjustment for patient
demographic, clinical, disease, and treatment characteristics, alvimopan use was associated with a significantly faster return of bowel
function and fewer incidences of postoperative ileus, indwelling
Foley catheter re-insertion, and postoperative urinary tract infection.
Hospital length of stay was significantly shorter in the alvimopan
group (1.6 days, P ¼ 0.002), without an increase in 30-day readmission rate (P ¼ 0.69). With adjustment, alvimopan treatment was
associated with a significant reduction in patient care costs ($1261,
P < 0.001) and even pharmacy-related costs (–$187, P ¼ 0.03),
amounting a total of hospital cost savings of $1492 per patient. This
suggests that alvimopan is cost-effective in the setting of enhanced
recovery protocols, offsetting the cost of this medication by a large
margin. Therefore, adding alvimopan to enhanced recovery colorectal surgery programs may provide significant improvement in
outcomes and hospital cost savings.
TABLE 2. Unadjusted Short-term Outcomes in Patients Treated With Alvimopan Versus Control
Outcomes
EBL [ml, median (IQR)]
ROBF [days, median (IQR)]
Postoperative ileus
Foley removal [days, median (IQR)]
Foley catheter re-insertion
Urinary tract infection
Length of stay [days, median (IQR)]
30-day readmission
Control (N ¼ 463)
113
2
74
2
64
57
5
57
(50–300)
(1–3)
(16%)
(2–3)
(14%)
(12%)
(4–7)
(12%)
Alvimopan (N ¼ 197)
100
2
9
2
13
10
4
19
(50–300)
(1–2)
(5%)
(2–3)
(7%)
(5%)
(3–6)
(10%)
P Value
0.14
0.03
<0.0001
0.94
0.008
0.005
0.0002
0.35
EBL indicates estimated blood loss; IQR, interquartile range; POD, postoperative day; ROBF, return of bowel function.
ß
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.annalsofsurgery.com | 3
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
ANNSURG-D-15-00873; Total nos of Pages: 6;
ANNSURG-D-15-00873
Annals of Surgery Volume XX, Number X, Month 2015
Adam et al
TABLE 3. Summary of Multivariable Short-term Outcomes Analyses Examining the Adjusted Association of Each Outcome
With Alvimopan Treatment Versus Control
Return of bowel function
Postoperative ileus
Length of hospital stay
30-day readmission
Mean Difference
OR (95 CI)
P Value
0.6 days
–
1.6 days
–
–
0.23 (0.11–0.50)
–
0.89 (0.50–1.58)
0.0006
0.0002
0.002
0.69
Outcomes were examined in different multivariable models with adjustment for patient age, sex, race, BMI, ASA scores, diagnosis, extent of surgery, use of laparoscopy and
epidural, and operating surgeon.
CI indicates confidence interval; OR, odds ratio.
TABLE 4. Unadjusted Costs in Patients Treated With Alvimopan Versus Control
Control (N ¼ 463)
Patient care cost
Diagnostic cost
Operative cost
Pharmacy cost
Total hospital costs
$2349
$358
$5507
$786
$9507
Alvimopan (N ¼ 197)
(1565–3873)
(209–789)
(4593–6762)
(573–1164)
(7658–12,171)
$1890
$396
$5558
$722
$8749
(1339–2597)
(168–869)
(4762–6592)
(568–952)
(7594–10,853)
P Value
0.0002
0.85
0.77
0.04
0.02
Costs data are presented as median (interquartile range).
Although there are robust randomized and retrospective data
that established the beneficial effect of alvimopan on reducing
postoperative ileus, hospitalization, and hospital costs after bowel
resection in general,14,15,26– 29 these beneficial effects of alvimopan
may not be generalizable in a setting of enhanced recovery colorectal
surgery protocol. Patients undergoing colorectal surgery under
enhanced recovery protocols are well optimized with a significantly
decreased postoperative morbidity and length of hospitalization.
Therefore, alvimopan may not add a clinically significant improvement in these already well-optimized patients. Published data examining the role of alvimopan in the setting of enhanced recovery
colorectal surgery have largely shown its ability to decrease
FIGURE 1. Adjusted analyses examining association of alvimopan treatment versus control and hospital costs. Data are
presented as adjusted mean differences. Each cost measure
was examined in a separate multivariable model with adjustment for patient age, sex, race, BMI, ASA scores, diagnosis,
history of opioid use, year of procedure, extent of surgery, use
of laparoscopy and epidural, and operating surgeon.
4 | www.annalsofsurgery.com
postoperative ileus. However, the reported effect of alvimopan on
hospital length of stay and costs has been inconsistent.17–19 Some of
these studies are limited by small sample size, precluding adequate
adjustment for important confounders, such as comorbidities and
extent of resection. Kelley et al19 examined the effect of alvimopan in
90 patients who had minimally invasive colorectal surgery under
enhanced recovery protocol at a single institution. The study
included 26 patients who were treated with alvimopan and 64
patients in the control group. In unadjusted analysis, the alvimopan
group had a significantly shorter time to tolerance of soft diet
(median 2 days vs 3 days, P ¼ 0.02) and return of bowel function
(median 1 day vs 2 days, P ¼ 0.003); hospital length of stay was
significantly shorter in the alvimopan group (median 3 days vs 4
days, P ¼ 0.02). In a larger single-institutional study, Obokhare
et al18 examined the effect of alvimopan on 100 patients who had
laparoscopic colectomy against a similar number of a matched
control. The patients were matched by age, sex, and diagnosis. They
found that patients on alvimopan were significantly less likely to
develop postoperative ileus (4% vs 12%, P ¼ 0.04); however, length
of stay was similar between the 2 groups (3.6 days vs 3.8 days,
P ¼ 0.84).
In our study, the use of alvimopan use was independently
associated with faster return of bowel function, fewer incidences of
postoperative ileus, and shorter hospitalization by 1.6 days.
Additionally, our study included patients who had open and laparoscopic colorectal resections; multivariable adjustment controlled for
possible effects of laparoscopic approach on outcomes of interest.
The large sample size allowed adequate control for other important
confounders, such patients’ demographics, comorbidities
(represented by ASA score), history of opioid use, diagnosis, extent
of resection, use of epidural analgesia, and operating surgeon—a
limitation of previous studies.
Our demonstrated benefit of alvimopan on reducing incidence
of postoperative ileus and hospital length of stay are consistent with
previous data from randomized clinical trials that examined the effect
of alvimopan in patients undergoing bowel resection. In a pooled
analysis of phase III randomized clinical trials, Delaney et al30
demonstrated that alvimopan versus control was associated with
significant reduction in rate of prolonged hospital length of stay (7%
vs 14%, P ¼ 0.002). Our study suggests that the benefit of alvimopan
ß
2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
ANNSURG-D-15-00873; Total nos of Pages: 6;
ANNSURG-D-15-00873
Annals of Surgery Volume XX, Number X, Month 2015
in these trails can be extended to enhanced recovery colorectal
surgery protocols.
In the current study, patients treated with alvimopan had a
lower incidence of postoperative urinary tract infection. This is likely
explained by the higher incidence of re-insertion of indwelling Foley
catheters in the control group. Patients with postoperative ileus are
dependent on intravenous hydration and urine output monitoring.
Prior studies have established the association between postoperative
ileus and urinary tract infection in patients undergoing colorectal
surgery.31
Limited data exist examining the cost-effectiveness of alvimopan in the setting of enhanced recovery colorectal surgery. In a
single-institution study of 90 patients undergoing minimally invasive
colectomy, hospital costs (reported as percentages) were examined
among patients who received alvimopan (n ¼ 26) versus those who
did not receive alvimopan (n ¼ 64). In unadjusted analysis, patient
care costs were significantly decreased in the alvimopan group (42%
vs 58%, P ¼ 0.02). Similarly, combined hospital costs were lower in
the alvimopan group, although it did not reach statistical significance
(46% vs 54%, P ¼ 0.09).19 With a large sample size, permitting
multivariable adjustment for confounders, we demonstrated that
alvimopan was associated with a statistically significant hospital
cost savings of $1492 per patient. This cost savings were largely
driven by reduction in patient care costs (–$1261), which is likely a
reflection of the lower incidence of postoperative ileus and shorter
length of hospitalization. In a large population-based study of 17,876
patients undergoing colectomy, postoperative ileus was associated
with a 1.6 days increase in hospital length of stay and a higher
hospital cost of $1461 per patient.3 It is also important to highlight
that despite the high cost of alvimopan, pharmacy-related costs were
reduced, underscoring the cost-effectiveness of this expensive medication. The decrease in pharmacy-related costs is likely driven by the
reduction in incidence of postoperative ileus, and the less use of
medications afforded by the shorter hospital length of stay.
Limitations to our study include those inherent to retrospective studies, such as the potential for selection bias. Expecting this
issue, we carefully adjusted for possible patient demographic and
clinical confounders. There could also be other unmeasured confounders that contributed to the reported effect of alvimopan; however, data utilized in this analysis were granular, permitting to adjust
for known confounders reported in the literature. Although data on
history of opioid use were not granular enough to definitively
determine appropriateness of alvimopan treatment, we have performed a subset analysis in which we excluded patients with a history
of preoperative opioid use. After exclusion of this group of
patients and with adjustment, alvimopan use remained significantly
associated with shorter length of stay and reduced hospital costs.
A portion of our control group was historical, from a year
behind. However, year of the procedure was controlled for in our
multivariable analyses.
CONCLUSIONS
This large, single institutional study provides valuable information regarding the effect of alvimopan on hospital length of stay
and costs in the setting of enhanced recovery colorectal surgery
protocol. We attempted to address some of the methodological
limitations of the existing literature by adjusting for significant
patient demographic, medical, and surgical confounders, and
reported actual hospital costs. We demonstrated that the addition
of alvimopan to an enhanced recovery colorectal surgery protocol is
associated with reduction in hospital length of stay and a significant
cost savings of $1492 per patients. As our health care system is
becoming more cost-conscious and quality-focused, utilization of
ß
2015 Wolters Kluwer Health, Inc. All rights reserved.
Alvimopan in Enhanced Recovery Colorectal Surgery
alvimopan can provide an opportunity for significant cost savings.
This is particularly important with knowing that there are more than
300,000 colorectal operations performed annually in the US. A cost
saving of $1492 per patient could translate into a significant cost
savings to the health care system. As such, we believe that alvimopan
should be considered as a part of enhanced recovery colorectal
surgery programs.
REFERENCES
1. Augestad KM, Delaney CP. Postoperative ileus: impact of pharmacological
treatment, laparoscopic surgery, and enhanced recovery pathways. World J
Gastroenterol. 2010;16:2067–2074.
2. Asgeirsson T, El-Badawi KI, Mahmood A, et al. Postoperative ileus: it costs
more than you expect. J Am Coll Surg. 2010;210:228–231.
3. Iyer S, Saunders WB, Stemkowski S. Economic burden of postoperative ileus
associated with colectomy in the United States. J Manag Care Pharm.
2009;15:485–494.
4. Delaney CP, Marcello PW, Sonoda T, et al. Gastrointestinal recovery after
laparoscopic colectomy: results of a prospective, observational, multicenter
study. Surg Endosc. 2010;24:653–661.
5. Madbouly KM, Senagore AJ, Delaney CP. Endogenous morphine levels after
laparoscopic versus open colectomy. Br J Surg. 2010;97:759–764.
6. Cali RL, Meade PG, Swanson MS, et al. Effect of Morphine and incision
length on bowel function after colectomy. Dis Colon Rectum. 2000;43:163–
168.
7. Varadhan KK, Neal KR, Dejong CH, et al. The enhanced recovery after
surgery (ERAS) pathway for patients undergoing major elective open colorectal surgery: a meta-analysis of randomized controlled trials. Clin Nutr.
2010;29:434–440.
8. Larson DW, Lovely JK, Cima RR, et al. Outcomes after implementation of a
multimodal standard care pathway for laparoscopic colorectal surgery. Br J
Surg. 2014;101:1023–1030.
9. Delaney CP, Zutshi M, Senagore AJ, et al. Prospective, randomized, controlled
trial between a pathway of controlled rehabilitation with early ambulation and
diet and traditional postoperative care after laparotomy and intestinal resection. Dis Colon Rectum. 2003;46:851–859.
10. Wind J, Polle SW, Fung Kon Jin PH, et al. Systematic review of enhanced
recovery programmes in colonic surgery. Br J Surg. 2006;93:800–809.
11. Gouvas N, Tan E, Windsor A, et al. Fast-track vs standard care in
colorectal surgery: a meta-analysis update. Int J Colorectal Dis. 2009;24:
1119–1131.
12. Greco M, Capretti G, Beretta L, et al. Enhanced recovery program in colorectal surgery: a meta-analysis of randomized controlled trials. World J Surg.
2014;38:1531–1541.
13. Miller TE, Thacker JK, White WD, et al. Reduced length of hospital stay in
colorectal surgery after implementation of an enhanced recovery protocol.
Anesth Analg. 2014;118:1052–1061.
14. Ludwig K, Enker WE, Delaney CP, et al. Gastrointestinal tract recovery in
patients undergoing bowel resection: results of a randomized trial of alvimopan and placebo with a standardized accelerated postoperative care pathway.
Arch Surg. 2008;143:1098–1105.
15. Delaney CP, Weese JL, Hyman NH, et al. Phase III trial of alvimopan, a novel,
peripherally acting, mu-opioid antagonist, for postoperative ileus after major
abdominal surgery. Dis Colon Rectum. 2005;48:1114–1125. discussion
1125–1126; author reply 1127–1129.
16. Hoffmann H, Kettelhack C. Fast-track surgery—conditions and challenges in
postsurgical treatment: a review of elements of translational research in
enhanced recovery after surgery. Eur Surg Res. 2012;49:24–34.
17. Itawi EA, Savoie LM, Hanna AJ, et al. Alvimopan addition to a standard
perioperative recovery pathway. JSLS. 2011;15:492–498.
18. Obokhare ID, Champagne B, Stein SL, et al. The effect of alvimopan on
recovery after laparoscopic segmental colectomy. Dis Colon Rectum.
2011;54:743–746.
19. Kelley SR, Wolff BG, Lovely JK, et al. Fast-track pathway for minimally
invasive colorectal surgery with and without alvimopan (Entereg): which is
more cost-effective? Am Surg. 2013;79:630–633.
20. Gustafsson UO, Scott MJ, Schwenk W, et al. Guidelines for perioperative care
in elective colonic surgery: Enhanced Recovery After Surgery (ERAS 1)
Society recommendations. World J Surg. 2013;37:259–284.
21. Nygren J, Thacker J, Carli F, et al. Guidelines for perioperative care in elective
rectal/pelvic surgery: Enhanced Recovery After Surgery (ERAS 1) Society
recommendations. World J Surg. 2013;37:285–305.
www.annalsofsurgery.com | 5
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
ANNSURG-D-15-00873; Total nos of Pages: 6;
ANNSURG-D-15-00873
Adam et al
22. National Institute for Health and Care Excellence. Ultrasound-guided catheterisation of the epidural space (2008). Available at: http://www.nice.org.uk/
guidance/ipg249/resources/guidance-ultrasoundguided-catheterisation-of-th
e-epidural-space-pdf. Accessed June 9, 2015.
23. Noblett SE, Watson DS, Huong H, et al. Pre-operative oral carbohydrate
loading in colorectal surgery: a randomized controlled trial. Colorectal Dis.
2006;8:563–569.
24. Habib AS, White WD, Eubanks S, et al. A randomized comparison of a
multimodal management strategy versus combination antiemetics for the prevention of postoperative nausea and vomiting. Anesth Analg. 2004;99:77–81.
25. Noblett SE, Snowden CP, Shenton BK, et al. Randomized clinical trial
assessing the effect of Doppler-optimized fluid management on outcome
after elective colorectal resection. Br J Surg. 2006;93:1069–1076.
26. Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan, a novel, peripherally
acting mu-opioid antagonist: results of a multicenter, randomized, doubleblind, placebo-controlled, phase III trial of major abdominal surgery and
postoperative ileus. Ann Surg. 2004;240:728–734. discussion 734–725.
6 | www.annalsofsurgery.com
Annals of Surgery Volume XX, Number X, Month 2015
27. Viscusi ER, Goldstein S, Witkowski T, et al. Alvimopan, a peripherally acting
mu-opioid receptor antagonist, compared with placebo in postoperative ileus
after major abdominal surgery: results of a randomized, double-blind, controlled study. Surg Endosc. 2006;20:64–70.
28. Buchler MW, Seiler CM, Monson JR, et al. Clinical trial: alvimopan for the
management of postoperative ileus after abdominal surgery: results of an
international randomized, double-blind, multicentre, placebo-controlled
clinical study. Aliment Pharmacol Ther. 2008;28:312–325.
29. Delaney CP, Craver C, Gibbons MM, et al. Evaluation of clinical outcomes
with alvimopan in clinical practice: a national matched-cohort study in
patients undergoing bowel resection. Ann Surg. 2012;255:731–738.
30. Delaney CP, Wolff BG, Viscusi ER, et al. Alvimopan for postoperative ileus
following bowel resection: a pooled analysis of phase III studies. Ann Surg.
2007;245:355–363.
31. Kang CY, Chaudhry OO, Halabi WJ, et al. Risk factors for postoperative
urinary tract infection and urinary retention in patients undergoing surgery for
colorectal cancer. Am Surg. 2012;78:1100–1104.
ß
2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.